The cephalosporin (6R,7R)-3-[5-Amino-4-[3-(2-aminoethyl)ureido]-1-methyl-1H-pyrazol-2-ium-2-ylmethyl]-7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(Z)-1-carboxy-1-methylethoxyimino]acetamido]-3-cephem-4-carboxylic acid (also referred to as “CXA-101” and previously designated FR264205) is an antibacterial agent. CXA-101 can be provided as the compound shown in FIG. 1. The antibacterial activity of CXA-101 is believed to result from its interaction with penicillin binding proteins (PBPs) to inhibit the biosynthesis of the bacterial cell wall which acts to stop bacterial replication. CXA-101 can be combined (e.g., mixed) with a β-lactamase inhibitor (“BLI”), such as tazobactam. Tazobactam is a BLI against Class A and some Class C β-lactamases, with well established in vitro and in vivo efficacy in combination with active β-lactam antibiotics. The combination of CXA-101 and tazobactam in a 2:1 weight ratio is an antibiotic pharmaceutical composition (“CXA-201”) for parenteral administration. CXA-201 displays potent antibacterial activity in vitro against common Gram-negative and selected Gram-positive organisms. CXA-201 is a broad-spectrum antibacterial with in vitro activity against Enterobacteriaceae including strains expressing extended spectrum β-lactamases-resistant (MIC90=1 μg/mL), as well as Pseudomonas aeruginosa (P. aeruginosa) including multi-drug resistant strains (MIC90=2 μg/mL). CXA-201 is a combination antibacterial with activity against many Gram-negative pathogens known to cause intrapulmonary infections, including nosocomial pneumonia caused by P. aeruginosa. 
Intrapulmonary infections, such as nosocomial pneumonia, remain a major cause of morbidity and mortality, especially infections caused by drug resistant pathogens such as P. aeruginosa. One challenge in treating intrapulmonary infections with systemic administration of an antibiotic is determining the antibiotic dose that will provide a therapeutically safe and effective concentration of the antibiotic at the site of an infection on the mucosal side of the bronchi in the lung (i.e., in the bronchial secretions). Many antibiotics diffuse poorly from the bloodstream across the bronchi [e.g., Pennington, J. E., “Penetration of antibiotics into respiratory secretions,” Rev Infect Dis 3(1):67-73 (1981)], which can result in the administration of higher doses of antibiotic than would be prescribed for a truly systemic infection. Furthermore, the purulent sputum that characterizes infected patients tends to compromise the potency of many antibiotics (See e.g., Levy, J., et al., “Bioactivity of gentamicin in purulent sputum from patients with cystic fibrosis or bronchiectasis: comparison with activity in serum,” J Infect Dis 148(6):1069-76 (1983)). In some cases, the result is the prescription of large amounts of a systemically administered antibiotic to treat an intrapulmonary infection.
The efficacy of an antibiotic depends in part on the concentration of the drug at the site of action. Efficacy of antimicrobial therapy requires adequate antibiotic concentrations at the site of bacterial infection, and some authorities believe that epithelial lining fluid (ELF) concentrations are a reasonable surrogate for predicting effective concentrations for treating intrapulmonary infections such as pneumonia. For many antibiotics, clinical data correlating ELF concentrations to clinical outcome is unavailable and the clinical significance of differences in pulmonary penetration of antibiotics is unknown or poorly characterized. Few studies have quantified the penetration of β-lactam agents into the lung, as measured by the ratio of area under the concentration-time curve (AUC) in ELF to AUC in plasma (AUC(ELF)/AUC(plasma) ratio). For some published studies, the concentration of antibiotics measured in the ELF of the lung has varied widely. For example, the reported penetration ratio of telavancin in healthy human volunteers ranges widely between 0.43 and 1.24 (Lodise, Gottfreid, Drumm, 2008 Antimicrobial Agents and Chemotherapy). Thus, predicting the penetration of a drug into the ELF a priori, based on the structure, molecular weight, size and solubility is difficult due to the limited data available on the effect of physicochemical properties on the lung penetration of drugs.
Accordingly, the efficacy of a particular drug in treating intrapulmonary infections, in particular nosocomial pneumonia, cannot be predicted solely on the basis of data, such as in vitro data relating to the activity of that drug against a particular bacterium, which does not give any indication as whether the drug will accumulate at a therapeutically safe and effective concentration at the site of an infection on the mucosal side of the bronchi in the lung (i.e., in the bronchial secretions). For instance, tigicycline, a glycylcycline antimicrobial, has in vitro activity against many species of Gram-positive and Gram-negative bacteria, including P. aeruginosa, and it has been approved by the FDA for the treatment of complicated skin and skin structure infections, complicated intra-abdominal infections, and community acquired pneumonia. However, tigicycline is not approved for the treatment of nosocomial pneumonia, in view of an increased mortality risk associated with the use of tigicycline compared to other drugs in patients treated for nosocomial pneumonia.